SirT1 regulates adipose tissue inflammation.
SirT1 regulates adipose tissue inflammation.
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DOI：
10.2337/db11-0616
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发表时间：
2011-12
期刊：
影响因子：
7.7
通讯作者：
Shulman GI
中科院分区：
文献类型：
--
作者：
Gillum MP;Kotas ME;Erion DM;Kursawe R;Chatterjee P;Nead KT;Muise ES;Hsiao JJ;Frederick DW;Yonemitsu S;Banks AS;Qiang L;Bhanot S;Olefsky JM;Sears DD;Caprio S;Shulman GI
巨噬细胞向脂肪组织的募集是肥胖的一个可重复的特征。然而，在能量过剩状态下导致趋化因子产生和巨噬细胞向脂肪组织募集的事件尚不清楚。Sirtuin 1（SirT1）是一种重要的营养敏感组蛋白脱乙酰酶，热量限制会使其增加，过度喂养会使其减少。我们发现SirT1的缺失通过刺激白色脂肪组织中炎症因子的产生而导致厌食症，从而证实了SirT1的减少与营养过剩和脂肪组织炎症有关。我们使用反义寡核苷酸将SirT1降低到与营养过剩期间所见水平相似的水平，并研究了SirT1过表达转基因小鼠和脂肪特异性SirT1敲除动物。最后，我们分析了两个独立的人类受试者队列的皮下脂肪组织活检。我们发现，体内SirT1的诱导性或遗传性减少导致巨噬细胞向脂肪组织募集，而SirT1的过表达阻止了由慢性高脂喂养引起的脂肪组织巨噬细胞积聚。我们还发现SirT1在人皮下脂肪中的表达与脂肪组织巨噬细胞浸润呈负相关。脂肪组织SirT1表达的减少导致组蛋白过度乙酰化和异位炎症基因表达，被鉴定为啮齿动物和人类营养过剩期间巨噬细胞流入脂肪组织的关键调节组分。我们的研究结果表明，SirT1调节脂肪组织炎症反应的诱导剂，如脂肪酸，缺氧，内质网应激通过控制促炎转录的增益。
Macrophage recruitment to adipose tissue is a reproducible feature of obesity. However, the events that result in chemokine production and macrophage recruitment to adipose tissue during states of energetic excess are not clear. Sirtuin 1 (SirT1) is an essential nutrient-sensing histone deacetylase, which is increased by caloric restriction and reduced by overfeeding. We discovered that SirT1 depletion causes anorexia by stimulating production of inflammatory factors in white adipose tissue and thus posit that decreases in SirT1 link overnutrition and adipose tissue inflammation. We used antisense oligonucleotides to reduce SirT1 to levels similar to those seen during overnutrition and studied SirT1-overexpressing transgenic mice and fat-specific SirT1 knockout animals. Finally, we analyzed subcutaneous adipose tissue biopsies from two independent cohorts of human subjects. We found that inducible or genetic reduction of SirT1 in vivo causes macrophage recruitment to adipose tissue, whereas overexpression of SirT1 prevents adipose tissue macrophage accumulation caused by chronic high-fat feeding. We also found that SirT1 expression in human subcutaneous fat is inversely related to adipose tissue macrophage infiltration. Reduction of adipose tissue SirT1 expression, which leads to histone hyperacetylation and ectopic inflammatory gene expression, is identified as a key regulatory component of macrophage influx into adipose tissue during overnutrition in rodents and humans. Our results suggest that SirT1 regulates adipose tissue inflammation by controlling the gain of proinflammatory transcription in response to inducers such as fatty acids, hypoxia, and endoplasmic reticulum stress.
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